Antipsychotic selection is important to reduce nonadherence in schizophrenia

Researchers conducted a nationwide, registry-based study of primary antipsychotic non-adherence in schizophrenia.

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“Mr. Spear” is a 43-year-old white male with a 20-year history of schizophrenia who presents for a first outpatient appointment with a chief complaint of insomnia. After further questioning, he explains that he is afraid to sleep due to paranoia because there are individuals outside his house at night who want to kill him. He will not take any medication that makes him drowsy. His mental state is otherwise unremarkable. He denies any suicidal or murderous thoughts and does not seem to pay attention to internal stimuli. He reports several previous psychiatric hospitalizations, but none in the last 3 years. He works full-time in construction and denies any work-related issues. After a discussion of the risks and benefits, he agrees to a trial of daily low dose aripiprazole (in the morning) and to return to the clinic in 4 weeks. However, Mr. Spear does not show up for his follow-up appointment, he does not return a phone call to reschedule, and he never returns to the clinic.

Decreased adherence to antipsychotic treatment is common in schizophrenia and associated with poorer outcomes, including disease relapse, cognitive impairment, substance use, suicide, and mortality.1.2 Estimates of adherence to antipsychotics in schizophrenia vary widely, and there is evidence that objective methods (eg, pharmacy refill records or blood levels) yield significantly lower adherence rates than measurements. subjective.3 Additionally, large sample sizes are required to compare adhesion rates between specific agents, which can be determined by the balance between efficacy and tolerability. A previous large-scale pharmacy renewal registry study from 1998 to 1999 in military veterans (primarily male) with schizophrenia found that compliance was highest for clozapine and lowest for quetiapine.4 It is not known whether compliance differs for newer oral antipsychotics or long-acting injectable agents (LAI).

The current study

Accordingly, Lieslehto et al5 conducted a national registry-based study of primary antipsychotic non-adherence in outpatients with schizophrenia. They included all people in Finland diagnosed with schizophrenia or schizoaffective disorder (International Classification of Diseases codes F20, F25 and 295) from 1972 to 2014 who were alive on January 1, 2015 and under the age of 65. They selected n=29,956 outpatients who had an electronic prescription (new or refill) for an antipsychotic (chemical therapeutic anatomical classification code N05A, excluding lithium) in 2015 to 2016 using Kanta, the Finnish e-prescription database. There are no missing data on electronic prescription dispensing.

The primary outcome was primary antipsychotic non-adherence, defined as an antipsychotic prescription that was not dispensed by the pharmacy within one year. The authors also compared nonadherence to antipsychotics with that of other drug groups, including oral antidiabetics, antihypertensives, and statins, in the same patients with schizophrenia. Covariates included age, gender, time since first diagnosis of schizophrenia, concomitant medications, medical comorbidities, history of suicide attempt, and substance use disorder. For each antipsychotic, the authors calculated the proportion of non-adherence (the number of prescriptions not dispensed divided by the total number of prescriptions) with 95% confidence intervals (CI). Odds ratios (ORs) and 95% CIs were calculated for sociodemographic and clinical factors associated with nonadherence to primary antipsychotics. They also tested whether primary adherence levels between oral antipsychotics vary with efficacy or tolerability.

The average age of the participants was 42 years old, 52% of the participants were men and 49% were diagnosed more than 20 years ago. The most common concomitant psychiatric medications were benzodiazepines and related drugs (47%), antidepressants (36%) and mood stabilizers (24%). Approximately 32% (n=9506) of subjects were non-compliant with antipsychotic medication (ie, at least 1 prescription not dispensed). In contrast, primary non-adherence was lower for antidiabetics (18%), antihypertensives (21%) and statins (14%) in patients with schizophrenia. Several factors were associated with primary nonadherence (Table 1), the strongest association being for age below 25 (OR, 1.77).

Benzodiazepines (OR, 1.47) and mood stabilizers (OR, 1.29) were also linked to primary nonadherence.

Overall, 7.4% of antipsychotic prescriptions were not dispensed (Table 2).

At the group level, there were more prescriptions not dispensed for oral antipsychotics (10.3%) than for LAIs (7.3%). Based on previous data, antipsychotic efficacy and tolerability were related to adherence, indicating that agents with fewer adverse effects and greater efficacy were more likely to be dispensed.6

Conclusions of the study

The study authors concluded that approximately 1 in 3 outpatients with schizophrenia had primary nonadherence to antipsychotics, which was greater than to their somatic medications (14% to 21%). Additionally, patients using clozapine had the lowest nonadherence, and patients using LAI antipsychotics had lower nonadherence than those using oral agents. Younger age, female gender, more recent diagnosis, and substance use were all associated with primary nonadherence. Strengths of the study included the use of a national sample and registry-based data. Limitations included a focus on primary nonadherence (eg, patients may not take prescribed antipsychotics).

The essential

Selection of antipsychotics should consider several factors, including efficacy, tolerability, route of administration, concomitant medications, and patient comorbidities, to minimize non-adherence and associated adverse effects.

Dr. Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University, Georgia. He is on the editorial board and is editor of the schizophrenia and psychosis section for Psychiatric timeMT. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.


1. Robinson D, Woerner MG, Alvir JM, et al. Predictors of relapse following a response to a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 1999;56(3):241-247.

2. Ward A, Ishak K, Proskorovsky I, Caro J. Adherence to atypical antipsychotic prescription refills and its association with the risks of hospitalization, suicide and death in patients with schizophrenia in Quebec and Saskatchewan: a retrospective database study. Clin Ther. 2006;28(11):1912-1921.

3. Velligan DI, Lam F, Ereshefsky L, Miller AL. Psychopharmacology: perspectives on medication compliance and atypical antipsychotics. Psychiatric service. 2003;54(5):665-667.

4. Valenstein M, Blow FC, Copeland LA, et al. Poor Adherence to Antipsychotics in Patients with Schizophrenia: Medications and Patient-Related Factors. Schizophrenic bull. 2004;30(2):255-264.

5. Lieslehto J, Tiihonen J, Lahteenvuo M, et al. Primary nonadherence to antipsychotic treatment in people with schizophrenia. Schizophrenic bull. 2022;48(3):655-663.

6. Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multiple episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019;394(10202):939-951. ❒

Martin E. Berry